Activation of certain N-arylacetamides and N-arylacetohydroxamic acids in relation to mammary gland tumorigenesis in the rat.
This report describes activation of certain N-aryl-acetamides and N-arylacetohydroxamic acids and its relationship to mammary gland tumorigenesis. Evidence is presented that metabolic activation of N-2-fluorenylacetamide (2-FAA) by mixed function oxidase of liver microsomes is the primary requirement for tumor induction in the mammary gland by this compound in young adult female rats. Mammary gland microsomes of those rats appear incapable of N-hydroxylating 2-FAA. Mammary gland microsomes of lactating rats, however, are capable of converting small amounts of 2-FAA to N-hydroxy-2-FAA, which suggests that the ability to perform certain metabolic activation reactions may depend on the stage of development of the mammary gland which is hormonally regulated. According to a current theory of chemical carcinogenesis, N-arylacetohydroxamic acids would have to be activated to electrophilic reactants to become ultimate carcinogens. Three mechanisms by which such reactants could be generated from N-aryl-acetohydroxamic acids in the mammary gland are reviewed: 1) nonenzymatic acetylation; 2) enzymatic N-O-acetyl transfer to form N-acetoxyarylamines; 3) one-electron oxidation to nitroxyl free radicals. In addition, the potential role of the metabolically formed glucuronide of N-hydroxy-2-FAA in mammary gland tumorigenesis is discussed.
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000378:metabolism*; D000230:Adenocarcinoma / Q000139:chemically induced; D000232:Adenofibroma / Q000139:chemically induced; D000236:Adenoma / Q000139:chemically induced; D000818:Animals; D001711:Biotransformation; D002273:Carcinogens; D003580:Cytochromes / Q000378:metabolism; D005260:Female; D006881:Hydroxyacetylaminofluorene / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced*; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
D002273:Carcinogens; D003580:Cytochromes; D006881:Hydroxyacetylaminofluorene; D015073:2-Acetylaminofluorene; D006899:Mixed Function Oxygenases; D009251:NADPH-Ferrihemoprotein Reductase